JNK regulates APP cleavage and degradation in a model of Alzheimer's disease

被引：141
作者：
Colombo, Alessio [1 ]
Bastone, Antonio [1 ]
Ploia, Cristina [1 ]
Sclip, Alessandra [1 ]
Salmona, Mario [1 ]
Forloni, Gianluigi [1 ]
Borsello, Tiziana [1 ]
机构：
[1] Ist Ric Farmacol Mario Negri, Dept Neurosci, Neural Death & Neuroprotect Unit, I-20157 Milan, Italy
来源：
NEUROBIOLOGY OF DISEASE | 2009年 / 33卷 / 03期
基金：
瑞士国家科学基金会;
关键词：
Alzheimer's disease; c-Jun N-terminal kinase; Amyloid-precursor protein; Oligomers; Phosphorylation; D-JNKI1; Intracellular signalling; AMYLOID PRECURSOR PROTEIN; N-TERMINAL KINASE; CELL-DEATH; DEPENDENT REGULATION; CYTOPLASMIC DOMAIN; PEPTIDE INHIBITOR; CEREBRAL-ISCHEMIA; ACOUSTIC TRAUMA; BETA; PHOSPHORYLATION;
D O I：
10.1016/j.nbd.2008.12.014
中图分类号：
Q189 [神经科学];
学科分类号：
071006 ;
摘要：
Secretion of Amyloid-beta peptide (A beta) circulating oligomers and their aggregate forms derived by processing of beta-amyloid precursor protein (APP) are a key event in Alzheimer's disease (AD). We show that phosphorylation of APP on threonine 668 may play a role in APP metabolism in H4-APP(sw) cell line, a degenerative AD model. We proved that INK plays a fundamental role in this phosphorylation since its specific inhibition, with the INK inhibitor peptide (D-JNKI1), induced APP degradation and prevented APP phosphorylation at T668. This results in a significant drop of beta APPs, A beta fragments and A beta circulating oligomers. Moreover the D-JNKI1 treatment produced a switch in the APP metabolism, since the peptide reduced the rate of the amyloidogenic processing in favour of the non-amyloidogenic one. All together our results suggest an important link between APP metabolism and the JNK pathway and contribute to shed light on the molecular signalling pathway of this disease indicating JNK as an innovative target for AD therapy. Published by Elsevier Inc.
引用
收藏
页码：518 / 525
页数：8
相关论文
共 28 条
[1]   Pin1 promotes production of Alzheimer's amyloid from β-cleaved amyloid precursor protein [J].
Akiyama, H ;
Shin, RW ;
Uchida, C ;
Kitamoto, T ;
Uchida, T .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2005, 336 (02) :521-529
[2]   Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of β-amyloid [J].
Ando, K ;
Iijima, K ;
Elliott, JI ;
Kirino, Y ;
Suzuki, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (43) :40353-40361
[3]  
Aplin AE, 1996, J NEUROCHEM, V67, P699
[4]   Novel strategy for treatment of viral central nervous system infection by using a cell-permeating inhibitor of c-Jun N-terminal kinase [J].
Beckham, J. David ;
Goody, Robin J. ;
Clarke, Penny ;
Bonny, Christophe ;
Tyler, Kenneth L. .
JOURNAL OF VIROLOGY, 2007, 81 (13) :6984-6992
[5]   Cell-permeable peptide inhibitors of JNK novel blockers of β-cell death [J].
Bonny, C ;
Oberson, A ;
Negri, S ;
Sauser, C ;
Schorderet, DF .
DIABETES, 2001, 50 (01) :77-82
[6]   A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia [J].
Borsello, T ;
Clarke, PGH ;
Hirt, L ;
Vercelli, A ;
Repici, M ;
Schorderet, DF ;
Bogousslavsky, J ;
Bonny, C .
NATURE MEDICINE, 2003, 9 (09) :1180-1186
[7]   Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans [J].
Brown, MS ;
Ye, J ;
Rawson, RB ;
Goldstein, JL .
CELL, 2000, 100 (04) :391-398
[8]   A transcriptively active complex of APP with Fe65 and histone acetyltransferase Tip60 [J].
Cao, XW ;
Südhof, TC .
SCIENCE, 2001, 293 (5527) :115-120
[9]   The TAT-JNK inhibitor peptide interferes with beta amyloid protein stability [J].
Colombo, A. ;
Repici, M. ;
Pesaresi, M. ;
Santambrogio, S. ;
Forloni, G. ;
Borsello, T. .
CELL DEATH AND DIFFERENTIATION, 2007, 14 (10) :1845-1848
[10]   D-JNKI1,a cell-penetrating c-Jun-N-terminal kinase inhibitor, protects against cell death in severe cerebral ischemia [J].
Hirt, L ;
Badaut, J ;
Thevenet, J ;
Granziera, C ;
Regli, L ;
Maurer, F ;
Bonny, C ;
Bogousslavsky, J .
STROKE, 2004, 35 (07) :1738-1743
123